Field of the Invention
This invention pertains to antibodies and fragments thereof having binding specificity to Tumor Necrosis Factor-alpha (hereinafter “TNF-α”). The invention also pertains to methods of screening for diseases and disorders associated with TNF-α, and methods of preventing or treating diseases and disorders associated with TNF-α by administering said antibodies or fragments thereof.
Description of Related Art
TNF-α is a pleiotropic cytokine produced by a variety of cells, including activated macrophages, monocytes, T and B lymphocytes, natural killer cells, astrocytes, endothelial cells, smooth muscle cells, some tumor cells, and epithelial cells. Monocytes, for instance, express at least five different molecular forms of TNF-α with molecular masses of 21.5-28 kDa which mainly differ by post-translational alterations such as glycosylation and phosphorylation. See U.S. Patent Application Publication No. 2007/0015699.
TNF-α is a member of the TNF-ligand superfamily which includes TNF-α, TNF-β (lymphotoxin-a), LT-b, OX40L, FASL, CD30L, CD27L, CD40L, and 4-1BBL. The ligands of the TNF ligand superfamily are acidic, share approximately 20% sequence homology in the extracellular domains, and exist as membrane-bound forms with the biologically active form being a trimeric/multimeric complex. For example, TNF-α and TNF-β share 32% amino acid sequence homology. See U.S. Pat. No. 5,891,679.
Two distinct forms of TNF-α exist, a 26 kDa membrane (233 amino acid) form and the soluble 17 kDa (157 amino acid) cytokine which is derived from proteolytic cleavage of the 26 kDa membrane form. The soluble (mature) TNF-α polypeptide is 157 amino acids long and is secreted after cleavage of a 76-residue peptide from the amino terminus of the pro-protein. TNF-α is active as a homotrimer, each monomer of 157 residues is folded into a “jelly roll” structure of antiparallel beta strands, contains a single, intramolecular disulfide bridge, and is a trimer in solution. Reed, et al. (October 1997) “Crystal structure of TNF-α mutant R31D with greater affinity for receptor R1 compared with R2.” Protein Eng. 10(10):1101-7; Eck and Sprang (October 1989) “The structure of tumor necrosis factor-alpha at 2.6 Å resolution. Implications for receptor binding” J. Biol. Chem., Vol. 264, Issue 29, 17595-17605; See U.S. Pat. No. 7,056,695.
TNF-α is a major mediator of inflammatory, immunological, and pathophysiological reactions. In vitro, TNF-α has diverse biological effects including the killing of transformed cells, stimulation of granulocytes and fibroblasts, damage to endothelial cells, psoriatic arthritis, and anti-parasitic effects. In vivo, TNF-α plays a key role as an endogenous mediator of inflammatory, immune and host defense functions and it is involved in a number of pathological conditions. TNF-α is capable of acting independently and in conjunction with other factors affecting a whole plethora of different body functions. These effects can either be beneficial or life-threatening to the host. Some of these effects are direct, others may be mediated via the induction of other secreted factors. See U.S. Pat. No. 5,891,679.
TNF-α exerts its biological effects through interaction with two distinct membrane TNF-α receptors, a 55 kDa species, designated p55 TNF-R and a 75 kDa species designated p75 TNF-R. The two TNF receptors exhibit 28% similarity at the amino acid level. This is confined to the extracellular domain and consists of four repeating cysteine-rich motifs, each of approximately 40 amino acids. Each motif contains four to six cysteines in conserved positions. See U.S. Pat. No. 7,056,695.
As set forth in greater detail below, TNF-α is believed to play a role in the development of a multitude of diseases and disorders, including but not limited to rheumatoid arthritis, psoriasis, asthma, Types I and II Diabetes, stroke, pulmonary fibrosis, depression and Alzheimer's disease. Due to the perceived involvement of TNF-α in a wide range of diseases and disorders, there remains a need in the art for compositions and methods useful for preventing or treating diseases associated with TNF-α, as well as methods of screening to identify patients having diseases or disorders associated with TNF-α. Particularly preferred anti-TNF-α compositions are those having minimal or minimizing adverse reactions when administered to the patient. Compositions or methods that reduce or inhibit diseases or disorders associated with TNF-α are beneficial to the patient in need thereof.